A phase 2 study of epothilone B analog BMS‐247550 (NSC 710428) in patients with relapsed aggressive non‐Hodgkin lymphomas

Churpek, Jane E.; Pro, Barbara; Besien, Koen van; Kline, Justin; Wade, James L.; Hagemeister, Fredrick B.; Karrison, Theodore; Smith, Sonali M.

doi:10.1002/cncr.27917

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…In recent years, macrocycles have emerged as one of the most promising categories of drug candidates for multiple indications. − Macrocyclic systems are restricted in their rotational and conformational freedom. While this property is actively exploited in the design of highly effective and specific compounds, the interdependency of rotatable bonds and other features such as bridged rings pose significant challenges to conformer ensemble generation.…”

Section: Resultsmentioning

confidence: 99%

Conformator: A Novel Method for the Generation of Conformer Ensembles

Friedrich

Flachsenberg

Meyder

et al. 2019

J. Chem. Inf. Model.

111

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Computer-aided drug design methods such as docking, pharmacophore searching, 3D database searching, and the creation of 3D-QSAR models need conformational ensembles to handle the flexibility of small molecules. Here, we present Conformator, an accurate and effective knowledgebased algorithm for generating conformer ensembles. With 99.9% of all test molecules processed, Conformator stands out by its robustness with respect to input formats, molecular geometries, and the handling of macrocycles. With an extended set of rules for sampling torsion angles, a novel algorithm for macrocycle conformer generation, and a new clustering algorithm for the assembly of conformer ensembles, Conformator reaches a median minimum root-mean-square deviation (measured between protein-bound ligand conformations and ensembles of a maximum of 250 conformers) of 0.47 Å with no significant difference to the highest-ranked commercial algorithm OMEGA and significantly higher accuracy than seven free algorithms, including the RDKit DG algorithm. Conformator is freely available for noncommercial use and academic research.

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Section: Resultsmentioning

confidence: 99%

Conformator: A Novel Method for the Generation of Conformer Ensembles

Friedrich

Flachsenberg

Meyder

et al. 2019

J. Chem. Inf. Model.

111

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“…A total of uninformative 11 trials were found, 7 for lack of appropriate follow-up, 4 for accrual failure and 0 for duplicity. 22,26,32,46,49,53,61,65,66,74,76 These trials represent 792 patients and 226 patient-years of involvement in which there was a minimum of 208 grade 3–4 severe adverse events (27.8%, 95% CI 22.4%–33.9%) and 7 deaths occurred (1.4%, 95% CI 0.8%– 2.7%). Among these patients, 175 experienced objective tumour response (24%, 95% CI 16.7%– 33.3%).…”

Section: Resultsmentioning

confidence: 99%

“…rituximab, which became available soon after this study was started). 46 A nonpositive phase 2 trial of soft tissue sarcoma included a subgroup of 8 responding patients with leiomyosarcoma. 18 This was followed by a trial in uterine leiomyosarcoma; the study was nonpositive and had lower response rate than the first trial.…”

Section: Discussionmentioning

confidence: 99%

Patient Benefit and Risk in Anticancer Drug Development: A Systematic Review of the Ixabepilone Trial Portfolio

Carlisle

Mattina

et al. 2019

Preprint

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OBJECTIVE: To describe the patient burden and benefit, and the dynamics of trial success in the development of ixabepilone, a drug that was approved in the US but not in Europe. DATA SOURCES: Trials were captured by searching Embase and MEDLINE on July 27, 2015. STUDY SELECTION: Inclusion: 1) primary trial reports, 2) interventional trials, 3) human subjects, 4) phase 1 to phase 3, 5) trials of ixabepilone in monotherapy or combination therapy of 6) pre-licensure cancer indications. Exclusion: 1) secondary reports, 2) interim results, 3) meta-analyses, 4) retrospective/observational studies, 5) laboratory analyses (ex vivo tissues), 6) reviews, 7) letters, editorials, guidelines, interviews, abstract-only and poster presentations. DATA EXTRACTION AND SYNTHESIS: Data were independently double-extracted and differences between coders were reconciled by discussion. MAIN OUTCOMES AND MEASURES: We measured risk using the number of drug-related adverse events that were grade 3 or higher, benefit by objective response rate and trial outcomes by whether studies met their primary endpoint with acceptable safety. RESULTS: We identified 39 publications of ixabepilone monotherapy and 23 primary publications of combination therapy, representing 5615 patients and 1598 patient-years of involvement over 11 years and involving 17 different malignancies. In total, 830 patients receiving ixabepilone experienced objective tumour response (16%, 95% CI 12.5%-20.1%), and 74 died from drug-related toxicites (2.2%, 95% CI 1.6%-2.9%). Responding indications and combinations were identified very quickly; thereafter, the search for additional responding indications or combinations did not lead to labelling additions. A total of 11 "uninformative" trials were found, representing 27% of studies testing efficacy, 208 grade 3-4 events and 226 patient-years of involvement (21% and 26% of the portfolio total, respectively). After the European Medicines Agency rejected ixabepilone for licensing, all further trial activity involving ixabepilone was pursued outside of Europe. DISCUSSION: Risk/benefit for patients who enrolled in trials of non-approved indications of ixabepilone did not improve over the course of the drug's development. Clinical value was discovered very quickly; however, a large fraction of trials were uninformative.

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“…Ixabepilone was well-tolerated, except for neuropathic toxicity. Considering that the response rate of ixabepilone is modest compared to other drugs currently in use, its use in lymphomas is very limited (Churpek, et al, 2013).…”

Section: Epothilonesmentioning

confidence: 99%